The mtDNA mutation spectrum of the progeroid polg mutator mouse includes abundant control region multimers

Siôn L. Williams, Jia Huang, Yvonne J.K. Edwards, Rick H. Ulloa, Lloye M. Dillon, Tomas A. Prolla, Jeffery M. Vance, Carlos T. Moraes, Stephan Züchner

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Polg mtDNA mutator mice are important models for investigating the role of acquired mtDNA mutations in aging. Despite extensive study, there remains little consensus on either the etiology of the progeroid phenotype or the mtDNA mutation spectrum induced by disrupted polymerase-γ function. To investigate the latter, we have developed a novel, pragmatic approach we term "Mito-seq," applying next-generation sequencing to enriched, native mtDNA. Regardless of detection parameters we observed an increase of at least two orders of magnitude in the number of mtDNA single nucleotide variants in Polg mutator mice compared to controls. We found no evidence for the accumulation of canonical mtDNA deletions but multimers of the mtDNA control region were identified in brain and heart. These control region multimers (CRMs) contained heterogeneous breakpoints and formed species that excluded the majority of mtDNA genes. CRMs demonstrate that polymerase-γ 3′-5′ exonuclease activity is required for preserving mtDNA integrity.

Original languageEnglish (US)
Pages (from-to)675-682
Number of pages8
JournalCell Metabolism
Volume12
Issue number6
DOIs
StatePublished - Dec 1 2010

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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